A truly preventive or targeted therapy against colon cancer does not yet exist. However, hormone replacement therapy in women unexpectedly resulted in reduced risk of colorectal cancer, use of oral contraceptives is associated with a lower incidence of this disease, and estradiol has been shown to reduce the formation of preneoplastic lesions in the colon. Estrogen receptor beta (ER) is the predominant estrogen receptor in the human colonic epithelium; polymorphisms in this gene are related to colon cancer incidence and its loss in tumors is related to advanced Dukes staging and poorer survival. In vivo mouse studies have demonstrated that ER agonist treatment prevents intestinal tumor development and that deletion of ER leads to an increase in colon adenomas. Collectively, these observations clearly point to a protective role for ER in colorectal cancer. Estrogen receptors have significant consequences in health and diseases. They can be activated or inactivated by ligands, and are ideal candidates for therapeutic targeting. Compounds exist that selectively activate ER, circumventing the adverse effects that estrogen induces in men and women through ER activation. As ER hold significant potential as a target for colon cancer therapy, it is essential to understand the basic mechanistic background of its action and to identify biomarkers of its activity. The PI's preliminary data supports the existence of three critical mechanisms whereby ER exerts these effects in the colon. These three mechanisms are 1) a predicted ER and PROX1 interaction, 2) an anti---inflammatory response via repression of NFkB/IL-6 signaling and 3) anti---oncogenic effects through the regulation of miRNA mediated pathways, including the miR17-92 and miR-200a/b clusters. This project takes advantage of the skills of the Center for Nuclear Receptors and Cell Signaling to provide a detailed understanding of ER's role and potential in colon cancer prevention and treatment. The overall objective of this project is to provide the mechanistic basis for novel colo cancer prevention and therapy utilizing ER.